Over 6 million new cases of sexually transmitted human papillomavirus (HPVs) infections are reported every year making HPV the most common sexually transmitted agent world-wide. At least 15 carcinogenic HPV types cause virtually all cervical cancers however;the costly HPV vaccine licensed in 2006 covers only HPV types 6/11/16/18 and has no therapeutic effect on established infections. Thus all women must continue routine cervical screening at a US cost of $4-5 billion annually. More importantly, the majority of women alive today are still at risk for developing cervical cancer. In addition, the current vaccine program presently leaves all men unprotected. Given these considerations and the fact that cervical cancer is a disease of disparities, it is unlikely that projected disease reductions will be realized with current strategies. Programs to characterize current US HPV vaccine implementation and effectiveness are needed and continuing efforts to better understand HPV biology and to develop broadly protective prevention strategies and therapeutics for existing infections remain critical. The specific aims of this application are: 1) To establish the University of New Mexico Interdisciplinary HPV Prevention Center that incorporates research approaches to address these gaps in knowledge. 2) To fund and support 4 projects representing a spectrum of interdisciplinary approaches including: A) modeling of PV-host interactions in 3 dimensions to define elements of epithelial cell biology and immunity that contribute to the pathogenesis and prevention of infections;B) utilizing novel vaccine strategies based on virus-display technology to generate broad protection against a majority of HPV infections;C) utilizing a unique bioinformatics system that captures all events of a US population-based cervical screening program to characterize implementation and effectiveness of primary and secondary HPV interventions;and D) developing a set of web-based tools to promote the informed adoption of HPV and other STI prevention. 3) To establish 2 cores housing shared resources to support these interdisciplinary research approaches: A) a biostatistics and bioinformatics core and B) a virus infection core supporting technologies for virus production, quantitation, and animal imaging and housing a biospecimen resource. PROJECT 1: GENITAL PAPILLOMAVIRUS INFECTIONS IN EPITHELIAL TISSUES (OZBUN, M.) PROJECT 1 DESCRIPTION (provided by applicant): Over 100 types of human papillomaviruses (HPVs) infect mucosal and cutaneous epithelium, causing benign and malignant tumors. About 6.2 million new cases of HPV sexually transmitted infections (STIs) are reported every year;>20 million people in the US are currently infected, and HPV is considered as the most common known STI worldwide. Overall, data suggest that a single sexual act can promote infection, indicating that the viruses are quite effective transmissible agents in vivo. Recently, we have been able to produce high-titer HPV stocks in the laboratory. Our studies using infectious HPV virions in cell culture studies and our colleagues'work with animal PVs indicate the viruses in general are poor at causing infections in vitro. We therefore postulate that the current monolayer cell culture PV infection model systems fail to accurately recapitulate the infectious process in vivo. Indeed, the major deficiencies in the study of genital HPV-related infections have included the lack of high titer infectious viral stocks and the lack of appropriate tissue-based model systems with which to study early infections, pathogenesis, and interventions. Our CENTRAL HYPOTHESIS is that monolayer cell cultures fail to display essential aspects of epithelial tissue HPV infections and important features of HPV infection establishment can be determined from 3-dimensional (3-D) tissue-based models. We will use high titer HPV virion stocks to pursue this program's goals, which are to establish more physiologically relevant 3-D tissue models of HPV genital infections and to answer basic and essential questions about the initiation of productive HPV infections. To address our central hypothesis, we will pursue SPECIFIC AIMS that encompass three biologically integrated, and increasingly complex systems with regard to sexually transmitted PV infections. In Aim 1 we will define requirements for HPV infection of cells in differentiated epithelium in vitro. In Aim 2 we will use a rodent genital infection model to identify the cell types that are susceptible to HPV infection and to further determine how wounding potentiates infection in vivo. In Aim 3 we will evaluate genital PV infection establishment in the context of our non-human model of STI HPV infections wherein primate anatomy and immune response can be assessed. Hypotheses regarding specific aspects of genital PV binding and infection are posed so that whether supported or refuted, we will increase our understanding of the molecular mechanisms of HPV-target cell interactions and the biology of epithelial tissue infection, areas vastly understudied. We expect this work will directly impact future development of broadly cross-protective prophylactic and therapeutic strategies for preventing persistent HPV STIs.